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. 2022 Mar 16:12:774202.
doi: 10.3389/fonc.2022.774202. eCollection 2022.

Identification of Germline Mutations in Upper Tract Urothelial Carcinoma With Suspected Lynch Syndrome

Bao Guan  1   2   3 , Jie Wang  1   2   3 , Xuesong Li  1   2   3 , Lin Lin  4 , Dong Fang  1   2   3 , Wenwen Kong  5 , Chuangyu Tian  5 , Juan Li  5 , Kunlin Yang  1   2   3 , Guanpeng Han  1   2   3 , Yucai Wu  1   2   3 , Yuhui He  1   2   3 , Yiji Peng  1   2   3 , Yanfei Yu  1   2   3 , Qun He  1   2   3 , Shiming He  1   2   3 , Yanqing Gong  1   2   3 , Liqun Zhou  1   2   3 , Qi Tang  1   2   3
Affiliations

Identification of Germline Mutations in Upper Tract Urothelial Carcinoma With Suspected Lynch Syndrome

Bao Guan et al. Front Oncol. .

Abstract

Objective: Whole-exon sequencing (WES) is a commercially available tool for hereditary disease testing. However, little is known about hereditary upper-tract urothelial carcinoma (UTUC) in the Chinese population. This study aims to investigate the prevalence of Lynch syndrome (LS) in UTUC patients with high-risk features and identify the germline mutations of genetic predisposition gene mutations in those patients.

Methods: In total, 354 consecutive UTUC patients undergoing surgery were universally recruited, of whom 108 patients under 60 years old or with a personal/family history of cancer underwent universal immunohistochemistry staining to detect the expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2). Patients with deficient or weak MMR protein staining or meeting the Amsterdam II criterion were defined as suspected LS patients, who further experienced microsatellite instability (MSI) (BAT25, BAT26, BAT40, D2S123, D5S346, D17S250) detection and performed WES analysis to explore germline pathogenic/likely pathogenic (P/LP) alterations.

Results: Of 108 patients, 90 (83.3%) cases were included due to younger than 60 years, and 18 cases due to personal/family history. IHC staining identified 21 patients with deficient MMR protein staining and 15 cases with weak MMR protein staining. Three cases met the Amsterdam II criterion but with proficient MMR protein staining. Finally, WES analysis was performed in 38 suspected LS patients and P/LP germline mutations were identified in 22 individuals. Genetic testing confirmed 5 LS cases, including 3 cases with novel mutations. MSI-harboring tumor was discovered in 4 LS cases, one of whom had weak MMR protein staining. Germline P/LP variants in DNA damage repair genes were found in 11 cases. In addition, we found that 11 patients had high- or moderate- penetrance P/LP mutations other than MMR genes. The common P/LP variants in high- or moderate-penetrance genes were 4 in ATM, 3 in MSH6 and KIT, and 2 in APC, NF1 and DICER.

Conclusions: We identified approximately 11% of UTUC cases as suspected LS and at least 1.4% patients with confirmed LS-associated UTUC. In addition, broader germline genetic testing could be considered to screen for cancer severity in hereditary UTUC patients.

Keywords: DNA mismatch repair; Lynch syndrome; inherited cancer; upper tract urothelial carcinoma; whole-exon sequence.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Flowchart of Lynch Syndrome screening. UTUC, upper tract urothelial carcinoma; MMR, mismatch repair; AMS, Amsterdam; WES, whole exon sequencing; LS-UTUC, Lynch Syndrome related UTUC.
Figure 2
Figure 2
Frequency and penetrance of germline pathogenic/likely pathogenic variants in patients with suspected LS-UTUC.
Figure 3
Figure 3
The germline variants distribution and clinicopathological features of LS-UTUC by literature review.
See this image and copyright information in PMC

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